User login
It’s too soon to discard cotesting in cervical cancer
In their new cervical cancer screening draft recommendation statement, the U.S. Preventive Services Task Force recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21-29 years, and either continuing 3-year cytology screening or 5-year high-risk human papillomavirus (HPV) screening in women aged 30-65 years.1 They arrived at the conclusion primarily based on an analysis of benefits and harms of each of the currently used screening modalities. Cytology plus HPV cotesting was considered but rejected based on the benefits versus harms calculations. However, some of the assumptions in their modeling are wrong and this has led them to faulty conclusions.
The USPSTF correctly identified CIN-2/3 and CIN-3+ detected and cervical cancer cases and deaths prevented as benefits. But they used the number of colposcopies and the number of tests conducted as their proxy for harms, primarily because these were more easily measured. They identified other harms, such as greater psychological distress related to being told of a positive HPV result (compared with being told of an abnormal cytology or cotest result), but these harms were not numerical and so they could not be incorporated into their modeling. They also did not measure the psychological distress associated with an extended screening interval or HPV-only screening.
The USPSTF also primarily relied on evidence from seven large, randomly controlled trials of primary screening, mostly conducted in Europe.3 Of the seven trials, two of them (SWEDESCREEN and POBASCAM) used HPV testing by a polymerase chain reaction methodology that is not approved by the U.S. Food and Drug Administration, not commercially available in the United States, and has different sensitivity and specificity does than FDA-approved tests.
Most of the studies also were done with conventional cytology that is, for the most part, no longer used in the United States. The age range in some of the studies was also very narrow (SWEDESCREEN evaluated women aged 32-38 years only) while extending to very young ages in others (ARTISTIC evaluated women as young as age 20 years). It may not be possible to extrapolate from these results to the U.S. experience. On the other hand, the USPSTF elected not to use data from very large retrospective U.S. trials, such as the data from more than 1 million women from Kaiser Permanente Northern California, which helped form the foundation of current guidelines.4
Although screening has dramatically reduced the incidence of cervical cancer in the United States, most screening in this country is opportunistic and lacks population-based registries or regular invitations to screening. The USPSTF notes that a sizable proportion of the U.S.-based female population is not routinely screened. In fact, 11.4% of 21- to 65-year-old women have not been screened in the previous 5 years and the percentages are higher among minority and disadvantaged populations. Although the numbers seem relatively small, more than half of women with cervical cancer are found in this population. These women also are at greater risk of being lost to follow-up. Unlike the patients in the European trials, there is no current mechanism in the United States to assure that patients will return in 5 years. In fact, the USPSTF notes this limitation in their evidence, but doesn’t provide a remedy. These women may not get rescreened for many years after the 5-year interval has passed, and there is no evidence that this interval is safe.
Finally, the USPSTF recommendations for HPV primary screening relied in whole or in part on cytology triage of positive results. There is no U.S. experience for the use of cytology within this context, and many experts have argued that the test performance of cytology in a triage setting would be different than in a screening setting and would further be different in a vaccinated population. Since the modeling on which these draft recommendations are based did not account for these changed performance characteristics, their assumptions must be wrong.
Five years have not yet passed since publication of the last set of guidelines, and we have no idea how this extended screening interval functions in our opportunistic screening system. Stated simply, these draft recommendations have gone too far and too fast and should be reconsidered.
Dr. Spitzer is a professor of obstetrics and gynecology at Hofstra Northwell School of Medicine, Hempstead, N.Y., and a past president of the American Society for Colposcopy and Cervical Pathology. He reported receiving royalties from Elsevier, and consulting fees from Hologic, Biop Medical, Illumigen, and Merck.
References
1. Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. September 2017.
2. Screening for Cervical Cancer in Primary Care: A Decision Analysis for the U.S. Preventive Services Task Force. 2017.
3. Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force. 2017.
4. J Natl Cancer Inst. 2014 Jul 18;106(8). pii: dju153.
In their new cervical cancer screening draft recommendation statement, the U.S. Preventive Services Task Force recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21-29 years, and either continuing 3-year cytology screening or 5-year high-risk human papillomavirus (HPV) screening in women aged 30-65 years.1 They arrived at the conclusion primarily based on an analysis of benefits and harms of each of the currently used screening modalities. Cytology plus HPV cotesting was considered but rejected based on the benefits versus harms calculations. However, some of the assumptions in their modeling are wrong and this has led them to faulty conclusions.
The USPSTF correctly identified CIN-2/3 and CIN-3+ detected and cervical cancer cases and deaths prevented as benefits. But they used the number of colposcopies and the number of tests conducted as their proxy for harms, primarily because these were more easily measured. They identified other harms, such as greater psychological distress related to being told of a positive HPV result (compared with being told of an abnormal cytology or cotest result), but these harms were not numerical and so they could not be incorporated into their modeling. They also did not measure the psychological distress associated with an extended screening interval or HPV-only screening.
The USPSTF also primarily relied on evidence from seven large, randomly controlled trials of primary screening, mostly conducted in Europe.3 Of the seven trials, two of them (SWEDESCREEN and POBASCAM) used HPV testing by a polymerase chain reaction methodology that is not approved by the U.S. Food and Drug Administration, not commercially available in the United States, and has different sensitivity and specificity does than FDA-approved tests.
Most of the studies also were done with conventional cytology that is, for the most part, no longer used in the United States. The age range in some of the studies was also very narrow (SWEDESCREEN evaluated women aged 32-38 years only) while extending to very young ages in others (ARTISTIC evaluated women as young as age 20 years). It may not be possible to extrapolate from these results to the U.S. experience. On the other hand, the USPSTF elected not to use data from very large retrospective U.S. trials, such as the data from more than 1 million women from Kaiser Permanente Northern California, which helped form the foundation of current guidelines.4
Although screening has dramatically reduced the incidence of cervical cancer in the United States, most screening in this country is opportunistic and lacks population-based registries or regular invitations to screening. The USPSTF notes that a sizable proportion of the U.S.-based female population is not routinely screened. In fact, 11.4% of 21- to 65-year-old women have not been screened in the previous 5 years and the percentages are higher among minority and disadvantaged populations. Although the numbers seem relatively small, more than half of women with cervical cancer are found in this population. These women also are at greater risk of being lost to follow-up. Unlike the patients in the European trials, there is no current mechanism in the United States to assure that patients will return in 5 years. In fact, the USPSTF notes this limitation in their evidence, but doesn’t provide a remedy. These women may not get rescreened for many years after the 5-year interval has passed, and there is no evidence that this interval is safe.
Finally, the USPSTF recommendations for HPV primary screening relied in whole or in part on cytology triage of positive results. There is no U.S. experience for the use of cytology within this context, and many experts have argued that the test performance of cytology in a triage setting would be different than in a screening setting and would further be different in a vaccinated population. Since the modeling on which these draft recommendations are based did not account for these changed performance characteristics, their assumptions must be wrong.
Five years have not yet passed since publication of the last set of guidelines, and we have no idea how this extended screening interval functions in our opportunistic screening system. Stated simply, these draft recommendations have gone too far and too fast and should be reconsidered.
Dr. Spitzer is a professor of obstetrics and gynecology at Hofstra Northwell School of Medicine, Hempstead, N.Y., and a past president of the American Society for Colposcopy and Cervical Pathology. He reported receiving royalties from Elsevier, and consulting fees from Hologic, Biop Medical, Illumigen, and Merck.
References
1. Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. September 2017.
2. Screening for Cervical Cancer in Primary Care: A Decision Analysis for the U.S. Preventive Services Task Force. 2017.
3. Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force. 2017.
4. J Natl Cancer Inst. 2014 Jul 18;106(8). pii: dju153.
In their new cervical cancer screening draft recommendation statement, the U.S. Preventive Services Task Force recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21-29 years, and either continuing 3-year cytology screening or 5-year high-risk human papillomavirus (HPV) screening in women aged 30-65 years.1 They arrived at the conclusion primarily based on an analysis of benefits and harms of each of the currently used screening modalities. Cytology plus HPV cotesting was considered but rejected based on the benefits versus harms calculations. However, some of the assumptions in their modeling are wrong and this has led them to faulty conclusions.
The USPSTF correctly identified CIN-2/3 and CIN-3+ detected and cervical cancer cases and deaths prevented as benefits. But they used the number of colposcopies and the number of tests conducted as their proxy for harms, primarily because these were more easily measured. They identified other harms, such as greater psychological distress related to being told of a positive HPV result (compared with being told of an abnormal cytology or cotest result), but these harms were not numerical and so they could not be incorporated into their modeling. They also did not measure the psychological distress associated with an extended screening interval or HPV-only screening.
The USPSTF also primarily relied on evidence from seven large, randomly controlled trials of primary screening, mostly conducted in Europe.3 Of the seven trials, two of them (SWEDESCREEN and POBASCAM) used HPV testing by a polymerase chain reaction methodology that is not approved by the U.S. Food and Drug Administration, not commercially available in the United States, and has different sensitivity and specificity does than FDA-approved tests.
Most of the studies also were done with conventional cytology that is, for the most part, no longer used in the United States. The age range in some of the studies was also very narrow (SWEDESCREEN evaluated women aged 32-38 years only) while extending to very young ages in others (ARTISTIC evaluated women as young as age 20 years). It may not be possible to extrapolate from these results to the U.S. experience. On the other hand, the USPSTF elected not to use data from very large retrospective U.S. trials, such as the data from more than 1 million women from Kaiser Permanente Northern California, which helped form the foundation of current guidelines.4
Although screening has dramatically reduced the incidence of cervical cancer in the United States, most screening in this country is opportunistic and lacks population-based registries or regular invitations to screening. The USPSTF notes that a sizable proportion of the U.S.-based female population is not routinely screened. In fact, 11.4% of 21- to 65-year-old women have not been screened in the previous 5 years and the percentages are higher among minority and disadvantaged populations. Although the numbers seem relatively small, more than half of women with cervical cancer are found in this population. These women also are at greater risk of being lost to follow-up. Unlike the patients in the European trials, there is no current mechanism in the United States to assure that patients will return in 5 years. In fact, the USPSTF notes this limitation in their evidence, but doesn’t provide a remedy. These women may not get rescreened for many years after the 5-year interval has passed, and there is no evidence that this interval is safe.
Finally, the USPSTF recommendations for HPV primary screening relied in whole or in part on cytology triage of positive results. There is no U.S. experience for the use of cytology within this context, and many experts have argued that the test performance of cytology in a triage setting would be different than in a screening setting and would further be different in a vaccinated population. Since the modeling on which these draft recommendations are based did not account for these changed performance characteristics, their assumptions must be wrong.
Five years have not yet passed since publication of the last set of guidelines, and we have no idea how this extended screening interval functions in our opportunistic screening system. Stated simply, these draft recommendations have gone too far and too fast and should be reconsidered.
Dr. Spitzer is a professor of obstetrics and gynecology at Hofstra Northwell School of Medicine, Hempstead, N.Y., and a past president of the American Society for Colposcopy and Cervical Pathology. He reported receiving royalties from Elsevier, and consulting fees from Hologic, Biop Medical, Illumigen, and Merck.
References
1. Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. September 2017.
2. Screening for Cervical Cancer in Primary Care: A Decision Analysis for the U.S. Preventive Services Task Force. 2017.
3. Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing: A Systematic Evidence Review for the U.S. Preventive Services Task Force. 2017.
4. J Natl Cancer Inst. 2014 Jul 18;106(8). pii: dju153.
Is excision required in adolescents with CIN 2 or higher on cervical cytology?
Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.
EXPERT COMMENTARY
Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.
As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.3
In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.
CIN 2 can be an unreliable diagnosis
Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues4 found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.
Details of the study
Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:
- Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
- Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
- Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
Regression more likely in adolescents
Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.
Approximately 80% of incident human papillomavirus (HPV) infections occur in adolescents and young women.5,6
From studies of women attending college, it has been learned that almost 40% of those who are uninfected at the time they enter college become infected within 24 months after matriculation and almost 60% become infected within 60 months.7,8
1. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescents and young women. J Pediatr. 1998;132:277-284.
2. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678-1683.
3. Ries LA, Eisner MP, Kosary CL. SEER cancer statistics review, 1973-1999. Bethesda, Md: National Cancer Institute; 2002.
4. Wright JD, Davila RM, Pinto KR, et al. Cervical dysplasia in adolescents. Obstet Gynecol. 2005;106:115-120.
5. Moscicki AB. Impact of HPV infection in adolescent populations. J Adolesc Health. 2005;37:S3-S9.
6. Weinstock H, Berman S, Cates W. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.
7. Winer RL, Lee SK, Hughes JP, Adams DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-226.
8. Richardson H, Kelsall G, Tellier P, et al. The natural history of type specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003;12:485-490.
Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.
EXPERT COMMENTARY
Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.
As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.3
In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.
CIN 2 can be an unreliable diagnosis
Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues4 found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.
Details of the study
Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:
- Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
- Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
- Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
Regression more likely in adolescents
Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.
Approximately 80% of incident human papillomavirus (HPV) infections occur in adolescents and young women.5,6
From studies of women attending college, it has been learned that almost 40% of those who are uninfected at the time they enter college become infected within 24 months after matriculation and almost 60% become infected within 60 months.7,8
Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.
EXPERT COMMENTARY
Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.
As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.3
In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.
CIN 2 can be an unreliable diagnosis
Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues4 found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.
Details of the study
Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:
- Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
- Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
- Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
Regression more likely in adolescents
Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.
Approximately 80% of incident human papillomavirus (HPV) infections occur in adolescents and young women.5,6
From studies of women attending college, it has been learned that almost 40% of those who are uninfected at the time they enter college become infected within 24 months after matriculation and almost 60% become infected within 60 months.7,8
1. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescents and young women. J Pediatr. 1998;132:277-284.
2. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678-1683.
3. Ries LA, Eisner MP, Kosary CL. SEER cancer statistics review, 1973-1999. Bethesda, Md: National Cancer Institute; 2002.
4. Wright JD, Davila RM, Pinto KR, et al. Cervical dysplasia in adolescents. Obstet Gynecol. 2005;106:115-120.
5. Moscicki AB. Impact of HPV infection in adolescent populations. J Adolesc Health. 2005;37:S3-S9.
6. Weinstock H, Berman S, Cates W. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.
7. Winer RL, Lee SK, Hughes JP, Adams DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-226.
8. Richardson H, Kelsall G, Tellier P, et al. The natural history of type specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003;12:485-490.
1. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescents and young women. J Pediatr. 1998;132:277-284.
2. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678-1683.
3. Ries LA, Eisner MP, Kosary CL. SEER cancer statistics review, 1973-1999. Bethesda, Md: National Cancer Institute; 2002.
4. Wright JD, Davila RM, Pinto KR, et al. Cervical dysplasia in adolescents. Obstet Gynecol. 2005;106:115-120.
5. Moscicki AB. Impact of HPV infection in adolescent populations. J Adolesc Health. 2005;37:S3-S9.
6. Weinstock H, Berman S, Cates W. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.
7. Winer RL, Lee SK, Hughes JP, Adams DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-226.
8. Richardson H, Kelsall G, Tellier P, et al. The natural history of type specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003;12:485-490.